It has been apparent for some years that a major etiologic risk factor for Crohn's disease (CD) is genetic susceptibility. There is clear increased familial aggregation and a number of genetic loci have been identified by genome-wide scans. A major advance was the identification of NOD2/CARD15 as the IBD1 gene, as it implicated the importance of the innate immune system in CD. However, while a number of genes are being identified that predispose to CD, we still know little of the genetic factors that determine the severity. Investigators in this PPG have demonstrated that the presence and magnitude of multiple CD-associated antibodies (ASCA, OMPC, 12) are associated with a more aggressive CD phenotype (termed CD-HighR). We have also demonstrated that at least one of these antibodies, ASCA, is familial, and while linked to specific regions of the genome, it is not linked/associated with NOD2/CARD15 in our data. The goal of this project is to identify the genes that underlie the expression of CD associated serum antibodies and the phenotypic spectrum of CD. We will use a large scale candidate gene approach, with the likely most relevant immunologic pathways (innate immunity, Th1 effector cells, regulatory T and B cells, and co-stimulatory pathways) being elucidated by other Projects in this PPG. To undertake such an approach we need the capability to do large scale genotyping, and to have both hypothesis generating and confirming stages. Both technology and patient resources are now available. Aim 1 is the hypothesis generating step, in which we will proceed to the identification of putative susceptibility genes for immuno-phenotypic subgroups of CD by performing a comprehensive association study in a case/control design. We will study approximately 225-300 genes, for an average of 10 markers per gene, which will be analyzed by a haplotype based approach that captures the common variation in a gene. The genes will be tested against the individual quantitative antibody levels and quartile sums. This will involve testing over 2300 markers, which will be accomplished using the high throughput technology of Illumina Corporation. Aim 2, is the hypothesis confirmatory step, in which the 15 "best" genes from Aim 1 will be tested in a second panel of subjects, an independent family based panel of CD "trios" (affected CD patients and both parents), that also numbers 1200 subjects. In Aim 3, the 3-5 best genes from Aim 2 will be sequenced for additional variation by examining individuals who are simultaneously from the extremes of the antibody distribution and share associated haplotypes of the associated candidate genes. Because of the resources of this PPG, this project provides a unique opportunity to identify genes that determine the severity of CD, thus providing insight into biological pathways potentially leading to improved therapeutics and even prevention.